Organocatalytic electrochemical amination of benzylic C–H bonds

Abstract

An organocatalytic site-selective electrochemical method for the benzylic C–H amination reactions of alkylarenes with azoles through hydrogen evolution has been developed. The protocol proceeds in an undivided cell under mild...

Direct Hydroxylarylation of Benzylic Carbons (sp3/sp2/sp) via Radical-Radical Cross-Coupling Powered by Paired Electrolysis

“…Similarly, switching to electron-neutral phenyl group resulted in a moderate yield (3h). Note that substrates with an electron-withdrawing group (EWG) were difficult to undergo benzylic C-H oxidation in previous reports 22,23 and we were satisfied to find that even EWG substituted 1i could afford the corresponding product 3i, albeit in a much lower yield. 4-tert-Butyltoluene could also smoothly participate in the reaction, providing the corresponding product 3j.…”

“…The benzylic C(sp 3 )-H is one of the most typical C-H bonds and exists in abundant chemicals, which is also present in many biologically active compounds 20 , and nearly 25% of the 200 best-selling drugs contain this structural moiety 21 . Lately, the electrochemical benzylic C(sp 3 )-H activation has been widely used for C-N 22 or C-O 23 coupling. However, to the best of our knowledge, the concurrent formation of C-C and C-O bond within one step through unactivated benzylic C(sp 3 )-H functionalization has rarely been reported.…”

“…In this context, we intended to make full utilization of the convergent paired electrolysis and the radical philicity 25 to realize the direct hydroxylarylation of unactivated benzylic C(sp 3 )-H without any external redox mediator. According to the previous literature 22,23 , we had noticed that it is feasible to oxidize the benzylic C(sp 3 )-H to benzylic C-radical under anodic oxidation, but this unstable intermediate can easily be further oxidized to benzyl carbocation 26 . Hence, we speculated as follows: the carbocation is nucleophilically attacked by water to form the corresponding benzylic alcohol, which is then further oxidized at the anode to generate the ketyl radical 27 .…”

Copper-Catalyzed Cross-Coupling of Benzylic C–H Bonds and Azoles with Controlled N-Site Selectivity

“…Recent efforts have begun prioritizing complementary methods for C­(sp 3 )–N coupling as a means to expand the topological diversity and physiochemical properties of the resulting molecules. , C–N coupling methods that directly functionalize C­(sp 3 )–H bonds bypass the need for pre-functionalized alkyl electrophiles and represent important targets for medicinal chemistry . Significant progress has been made in C­(sp 3 )–H amination reactions that install ammonia surrogates via nitrene transfer or azidation, while C–H/N–H cross-coupling reactions, for example, with secondary amines/amides or N–H heterocycles, are more limited and often require excess C–H substrate . Here, we report a copper-catalyzed method for selective cross-coupling of azoles with (hetero)­benzylic C–H substrates as the limiting reagent, affording N -benzylic heterocycles featured in pharmaceutical and agrochemical compounds (Figure A). − In addition to the challenge of C–H site selectivity, these reactions feature a second selectivity challenge arising from azoles that incorporate two (or more) nucleophilic nitrogen atoms .…”

Direct Hydroxylarylation of Benzylic Carbon (sp3/sp2/sp) via Radical-involved Paired Electrochemical Cascade Reaction

“…1A), which is also present in many biologically active compounds 23,24 , and nearly 25% of the 200 best-selling drugs contain this structural moiety 25 . Lately, the electrochemical benzylic C(sp 3 )-H activation has been widely used for C-N 26,27,28,29 or C-O 30 coupling. However, to the best of our knowledge, the formation of C-C bond through unactivated benzylic C(sp 3 )-H functionalization is rarely reported.…”